The Dynamics And Clinical Relevance Of Grey Matter And Periventricular White Matter Pathology In Multiple Sclerosis
Lead Research Organisation:
University College London
Department Name: Institute of Neurology
Abstract
About 130000 people in the UK have multiple sclerosis (MS) and, other than head injuries, it is the commonest cause of neurological disability in young adults, but we do not yet know its cause. The most obvious and most studied feature of MS is the presence of lesions in white matter (WM, the part of the brain that contains nerve fibres). WM lesions are seen where the covering (myelin) surrounding nerve fibres has been damaged or lost. They were the first feature of MS seen on brain scans, and it is now routine to look for WM lesions using magnetic resonance imaging (MRI) brain scans when making a diagnosis of MS. Their formation causes the episodes (termed relapses) of neurological symptoms that the majority of people with MS have initially, and we now have more than ten treatments available in the UK that can substantially reduce the risk of WM lesion formation and relapses. However, most people with MS eventually develop progressive disability without relapses, and the accumulation of WM lesions is only modestly related to this. We only have two treatments approved in the UK for progressive MS, and even these can only be given when there is MRI evidence for WM lesion activity or relapses. It is now thought that the loss of nerves cells is ultimately a more important cause of disability, but we do not know the main cause of nerve cell loss.
About two decades ago it become clear that grey matter (GM; the part of the brain that contains nerve cells) is significantly involved in MS. With advances in MRI, it became possible to measure shrinkage of the brain, mainly due to loss of GM (which is itself due to nerve cell damage and loss), and it was found that this is more closely related to MS disability progression than WM lesion formation. However, other aspects of GM damage, for example GM lesions (which are usually more extensive than WM lesions) remained difficult to detect. Recognising this, in 2010 we began a study to develop new MRI methods to look for GM disease in MS. We recruited over 200 people, including people with relapsing-remitting and progressive forms of MS, and people with no known neurological disease. We developed methods to better see GM lesions, and also to detect GM abnormalities beyond lesions. We also showed that MS disease effects were greater towards the surface of the brain both in GM and WM. Importantly, we found that these abnormalities were not closely linked with WM lesions and were independently associated with disability. As such, they could represent important targets for treatments. However, with the resources available at the time, we were only able to assess about a third of people over about 18 months, and so could not robustly look for changes over time or determine if they were - in the longer-term - closely linked with brain atrophy and disability.
The passage of a decade will have allowed changes in GM abnormalities to become clear, and their clinical significance to be more readily assessed, and so we now propose to follow up the people who took part in our original study. We will use updated MRI methods to look for GM and WM abnormalities, and specifically consider how WM and GM disease processes eventually lead to brain atrophy. We expect this work to provide valuable insights into the pathways leading to brain atrophy (and so nerve cell loss), and this should enable us to measure MS treatment effects on these pathways, rather than waiting for irreversible brain atrophy to occur. As we will use an MRI scanner similar to those already widely used in healthcare, we also expect this work to be quickly applicable in clinical trials (some of the methods we developed in our earlier study are already being used) and potentially in clinical practice.
About two decades ago it become clear that grey matter (GM; the part of the brain that contains nerve cells) is significantly involved in MS. With advances in MRI, it became possible to measure shrinkage of the brain, mainly due to loss of GM (which is itself due to nerve cell damage and loss), and it was found that this is more closely related to MS disability progression than WM lesion formation. However, other aspects of GM damage, for example GM lesions (which are usually more extensive than WM lesions) remained difficult to detect. Recognising this, in 2010 we began a study to develop new MRI methods to look for GM disease in MS. We recruited over 200 people, including people with relapsing-remitting and progressive forms of MS, and people with no known neurological disease. We developed methods to better see GM lesions, and also to detect GM abnormalities beyond lesions. We also showed that MS disease effects were greater towards the surface of the brain both in GM and WM. Importantly, we found that these abnormalities were not closely linked with WM lesions and were independently associated with disability. As such, they could represent important targets for treatments. However, with the resources available at the time, we were only able to assess about a third of people over about 18 months, and so could not robustly look for changes over time or determine if they were - in the longer-term - closely linked with brain atrophy and disability.
The passage of a decade will have allowed changes in GM abnormalities to become clear, and their clinical significance to be more readily assessed, and so we now propose to follow up the people who took part in our original study. We will use updated MRI methods to look for GM and WM abnormalities, and specifically consider how WM and GM disease processes eventually lead to brain atrophy. We expect this work to provide valuable insights into the pathways leading to brain atrophy (and so nerve cell loss), and this should enable us to measure MS treatment effects on these pathways, rather than waiting for irreversible brain atrophy to occur. As we will use an MRI scanner similar to those already widely used in healthcare, we also expect this work to be quickly applicable in clinical trials (some of the methods we developed in our earlier study are already being used) and potentially in clinical practice.
Technical Summary
To date magnetic resonance imaging (MRI) studies in multiple sclerosis (MS) have mostly focused on white matter (WM), although over the past 20 years progress has been made developing methods to detect grey matter (GM) pathology. GM atrophy, and the neurodegeneration underlying it, is now thought to ultimately be the cause of most irreversible disability in MS. However, we still have very limited insights into the tempo of GM disease, how this relates to WM disease, its associations with disability progression, and the prognostic relevance of earlier GM pathology to subsequent clinical outcomes.
A decade ago we undertook a study assess GM disease in MS, and associations with clinical outcomes. We recruited 148 people with MS, 9 following a clinically isolated syndrome and 52 healthy controls. We improved the detection of GM lesions (using phase sensitive inversion recovery), and were able to identify gradients (using high resolution magnetisation transfer ratio imaging) in cortical GM pathology consistent with previous histopathological studies that had shown that GM lesions and neuronal loss was much more prominent close to the surface of the brain. We also showed that there are similar, but previously unrecognised, gradients in abnormalities in WM. We found associations between these MRI features and clinical outcomes (MS phenotype, level of neurological or cognitive impairments).
We now plan to follow-up this cohort to characterise in detail the evolution of these MRI features, to assess how GM and WM MRI-visible pathology evolves, unpick pathways linking WM and GM pathology (using conventional statistical and structural equation modelling approaches), and determine how this translates into GM atrophy and disability. We will also asses the role factors such as iron deposition and hypo-perfusion, that have developed as significant MS research themes since our original study, could play in promoting cortical neurodegeneration.
A decade ago we undertook a study assess GM disease in MS, and associations with clinical outcomes. We recruited 148 people with MS, 9 following a clinically isolated syndrome and 52 healthy controls. We improved the detection of GM lesions (using phase sensitive inversion recovery), and were able to identify gradients (using high resolution magnetisation transfer ratio imaging) in cortical GM pathology consistent with previous histopathological studies that had shown that GM lesions and neuronal loss was much more prominent close to the surface of the brain. We also showed that there are similar, but previously unrecognised, gradients in abnormalities in WM. We found associations between these MRI features and clinical outcomes (MS phenotype, level of neurological or cognitive impairments).
We now plan to follow-up this cohort to characterise in detail the evolution of these MRI features, to assess how GM and WM MRI-visible pathology evolves, unpick pathways linking WM and GM pathology (using conventional statistical and structural equation modelling approaches), and determine how this translates into GM atrophy and disability. We will also asses the role factors such as iron deposition and hypo-perfusion, that have developed as significant MS research themes since our original study, could play in promoting cortical neurodegeneration.
